Intermittent Hypoxia Protects Brain from Ethanol Withdrawal Mechanisms and Therap

间歇性缺氧保护大脑免受乙醇戒断机制和治疗

基本信息

批准号：
8039278
负责人：
Marianna E Jung
金额：
$ 17.42万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-05 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8039278
关键词：
Abbreviations Abstinence Acute Adverse effects Alcohol consumption Alcohol withdrawal syndrome Alcoholic Intoxication Alcoholism Animals Apoptosis Apoptotic Attenuated Behavior Behavioral Benzodiazepines Brain Brain Injuries Brain region Cell Death Cell Hypoxia Cerebellum Clinical Convulsions DNA Fragmentation DNA Nucleotidylexotransferase Data Dependency Development Diet Distress Drug Metabolic Detoxication Ethanol Fluorescein Foundations Hippocampus (Brain)Hypoxia Immunohistochemistry Impairment In Situ Nick-End Labeling Label MAPK14 gene Measures Mediating Memory Methods Modeling Neurologic Oxidative Stress Oxygen Patients Phase Phenotype Phosphotransferases Pilot Projects Play Rattus Role SB 203580 Swelling Swimming Testing Time Tremor Ventilatory Depression Water Withdrawal alcohol exposure caspase-3 clinical application conditioning cytotoxicity drinking effective therapy experience falls inhibitor/antagonist male mitochondrial membrane prevent problem drinker public health relevance research study response retinal rods

项目摘要

DESCRIPTION (provided by applicant): The cessation of ethanol consumption is difficult and often unsuccessful, even for highly motivated patients. Abrupt termination of ethanol-exposure renders the brain vulnerable to neurological sequelae, including sensorimotor impairment, tremor, and convulsions, which discourage the patient's efforts to stop consuming alcohol. The only available treatment for the ethanol withdrawal (EW) distress is benzodiazepines but the side effects (e.g. dependency and respiratory depression) limit clinical use of this treatment. In a rat model of ethanol intoxication and withdrawal, we recently demonstrated profound brain protection by daily cycles of 5-10 minutes, intermittent, normobaric, moderate (FIO2 9.5-10%) hypoxia (IH). In our pilot studies, when IH treatment was applied during the last 20 days of an ethanol diet, it attenuated the overt behavioral signs of EW (e.g. tremor and rigidity); EW-induced mitochondrial membrane swelling; and cytotoxicity. In particular, EW provoked a more than 6-fold increase in the proapoptotic kinase P38; IH conditioning almost completely suppressed this increase in ethanol withdrawn rats. Interestingly, all of these IH protections were more effective during EW than during ethanol-exposure, implicating that IH counteracts factors mediating EW. These remarkable results suggest that adaptation to intermittent normobaric hypoxia could provide a safe and effective treatment complementary to conventional benzodiazepines. Using a repeated withdrawal paradigm, we intend to define behavioral phenotypes of IH protection with various treatment windows of IH and cellular mechanisms involving P38 by which IH protects against repeated EW. We hypothesize that IH conditioning applied during the initial cycle of EW exerts persistent protection against behavioral and brain injury throughout repeated EW. Rats will receive two cycles of an ethanol diet (7.5%) for 5 weeks and abrupt withdrawal for 20 days. IH conditioning will be applied to the initial cycle of the EW or the ethanol-exposure phase. We will determine 1) whether IH treatment during the initial cycle of EW protects against overt behavioral signs of EW and cerebellum-/hippocampus-related behavioral deficit and whether the protection persists throughout the repeated EW; 2) whether IH-induced suppression of P38 activity mediates protection against apoptotic (programmed cell death) brain injury and whether the protection persists throughout the repeated EW in a manner that correlates with behavioral protection. Some animals will receive the P38 inhibitor SB203580 to define the role of P38-inhibition in the IH protection. Defining the IH-induced behavioral and brain protection against EW insults and identifying an optimal treatment window may establish foundation data necessary for the development of an alternative management of EW. PUBLIC HEALTH RELEVANCE: Alcoholics failed to achieve complete abstinence due to distress associated with sudden termination of drinking. We observed that cycles of intermittent brief (5 to 8 min) and moderate hypoxia (9 to 10% oxygen) conditioning reduced signs of ethanol withdrawal (e.g. tremor and rigidity) and oxidative stress in rats. Information on intermittent hypoxia-evoked brain protection from ethanol withdrawal distress resulting will establish an empirical foundation to support eventual clinical application for a better management of alcoholism in which ethanol withdrawal plays a key role.

描述（由申请人提供）：即使对于积极性很高的患者来说，停止乙醇消费也很困难并且常常不成功。突然停止接触乙醇会使大脑容易出现神经系统后遗症，包括感觉运动障碍、震颤和抽搐，这会阻碍患者戒酒的努力。治疗乙醇戒断 (EW) 困扰的唯一可用治疗方法是苯二氮卓类药物，但副作用（例如依赖性和呼吸抑制）限制了这种治疗的临床使用。在乙醇中毒和戒断的大鼠模型中，我们最近证明了通过每天 5-10 分钟、间歇性、常压、中度（FIO2 9.5-10%）缺氧（IH）周期可以产生深刻的脑保护作用。在我们的试点研究中，当在乙醇饮食的最后 20 天进行 IH 治疗时，它减弱了 EW 的明显行为症状（例如震颤和僵硬）；电击引起的线粒体膜肿胀；和细胞毒性。特别是，EW 使促凋亡激酶 P38 增加了 6 倍以上； IH 调节几乎完全抑制了乙醇戒断大鼠的这种增加。有趣的是，所有这些 IH 保护在 EW 期间比乙醇暴露期间更有效，这表明 IH 抵消了介导 EW 的因素。这些显着的结果表明，适应间歇性常压缺氧可以提供一种安全有效的治疗方法，作为传统苯二氮卓类药物的补充。使用重复戒断范例，我们打算通过各种 IH 治疗窗口和涉及 P38 的细胞机制来定义 IH 保护的行为表型，IH 通过这些机制防止重复 EW。我们假设在 EW 初始周期中应用的 IH 调节在整个 EW 重复过程中对行为和脑损伤发挥持续的保护作用。大鼠将接受两个周期的乙醇饮食（7.5%），为期 5 周，然后突然停药 20 天。 IH 调节将应用于 EW 或乙醇暴露阶段的初始循环。我们将确定 1) EW 初始周期期间的 IH 治疗是否可以防止 EW 的明显行为迹象和小脑/海马相关的行为缺陷，以及这种保护作用是否在重复的 EW 中持续存在； 2) IH 诱导的 P38 活性抑制是否介导针对细胞凋亡（程序性细胞死亡）脑损伤的保护，以及这种保护是否以与行为保护相关的方式在重复的 EW 中持续存在。一些动物将接受 P38 抑制剂 SB203580 以确定 P38 抑制在 IH 保护中的作用。定义 IH 引起的行为和大脑针对 EW 损伤的保护并确定最佳治疗窗口可以为开发 EW 替代管理建立必要的基础数据。公共卫生相关性：酗酒者由于突然停止饮酒而感到痛苦，未能完全戒酒。我们观察到，间歇性短暂（5至8分钟）和中度缺氧（9%至10%氧气）调节循环可减少大鼠的乙醇戒断症状（例如震颤和僵硬）和氧化应激。关于间歇性缺氧引起的大脑保护免受乙醇戒断困扰的信息将为支持最终的临床应用建立一个经验基础，以更好地管理酒精中毒，其中乙醇戒断起着关键作用。